The invention relates to a fibrinogen-based tissue adhesive.
Fibrinogen-based tissue adhesives which can also be called fibrin adhesives, in their adhesive action imitate the final phase of blood coagulation. In this instance, fibrinogen is cleaved into fibrin monomers by the action of thrombin which mostly is added to the fibrinogen solution during the gluing procedure, which, however, is also present in every wound. The fibrin monomers agglomerate spontaneously to arranged fiber-type structures called fibrin. This fibrin monomer aggregate then is further stabilized under the action of factor XIIIa by covalent cross linking. At this, in a transamidizing reaction, peptide bonds form between specific glutamine and lysine side chains of the fibrin monomers. The factor XIIIa which likewise is cleaved by thrombin from inactive factor XIII is an active transamidase and, on account of its action, it is also called “fibrin-stabilizing factor”.
Although, when applying a tissue adhesive, in principle the same processes occur as in “natural” blood coagulation, in a tissue adhesive the participating components and factors are more concentrated by a multiple than in blood. Due to this, the coagulation of blood also occurs much more rapidly, and the achieved tissue sealing or the formed blood clot are much safer and also more stable.
A prerequisite for the breakthrough of the fibrin adhesives at the end of the 70's was the progress in the fractionation and purification of blood coagulation factors. Because of this it was possible to prepare the natural coagulation factors with such purity and at such a concentration as is required for an efficient tissue adhesion. The first commercially available tissue adhesives were launched on the market at the end of the 70's, and since then they have proven suitable in a large number of possible fields of application; primarily in those fields in which the use of conventional surgical techniques repeatedly have resulted in severe problems, e.g. with severe hemorrhages, when gluing nerves or when inner organs, such as the liver and spleen, were torn.
A further advantage of a fibrin adhesive in contrast to sutures using needle and thread resides in that the tissue or organ to be treated is not additionally damaged by the sewing procedure, and therefore, when using tissue adhesives based on fibrinogen, there are much fewer complications and less obtrusive scars than with conventional surgical sutures. Besides the optimum adhesive effect which comprises a high load bearing capacity and a high inner strength of the sealing as well as a good adherence of the adhesive to the wound or tissue surfaces, respectively, also the processes immediately following adhesion are essential for optimizing tissue adhesives (cf. AT-B-359 652 and 359 653). Among them are the control of the durability of the sealant within the body as well as their capability of being absorbed and the adhesive's properties of enhancing wound healing.
Therefore, for a tissue adhesive not only the rapid and secure sealing effect is of decisive importance but also that the sealant formed or the blood clot formed, respectively, dissolve again in the body within a certain period of time and the wound completely heals up as a consequence of the complete absorption of the formed clot.
In this connection, it is necessary to also control, the (endogenous) process of dissolving the formed blood clot, i.e. the fibrinolysis, by optimizing the tissue adhesive.
In fibrinolysis, the fibrin present in the blood clot formed is degraded and/or removed, and thereby the blood clot is dissolved. At first, under the influence of intrinsic or extrinsic plasminogen activators, such as blood coagulation factors XI and XII, prekallikrein, urokinase or t-PA, the fibrinolytically active plasmin is formed from the inactive plasminogen, said plasmin also cleaving fibrinogen and the blood coagulation factors V and VIII in addition to fibrin.
Since the endogenous fibrinolysis processes mostly start immediately after formation of a clot and thus there is a risk that an existing tissue sealant will not adhere good enough or that a clot formed will become destabilized too early, it has become a rule in tissue gluing to provide for the addition of a plasmin inhibitor or a plasminogen activator inhibitor so as to inhibit the action of plasmin directly or indirectly, to thus protect the sealant, primarily in its initial phase, from a premature fibrinolysis. With the concentration of the inhibitor also a targeted control of the dissolution times (lysis times) of the clot formed or of the sealant, respectively, is possible. The larger the amount of inhibitor provided, the more stable the clot relative to fibrinolysis, i.e., the longer will this clot remain stable and the longer will it take for the adhesive to be completely absorbed.
Thus, when using the fibrinolysis inhibitor, an optimum balance must be found between preventing premature fibrinolysis and an as rapid as possible wound healing process.
In the commercially available tissue adhesives, aprotinin is used as the plasmin inhibitor, which is also called bovine basic pancreatic trypsin inhibitor. Aprotinin is a polyvalent proteinase (kallikrein) inhibitor and inhibits coagulation factors XIIa, XIa, VIIIa as well as, primarily, plasmin and plasmin activators, but also trypsin, chymotrypsin and kallikrein.
Previously, aprotinin has mainly been produced from cattle. Due to the problems involved in the use of bovine material in medicaments which are used for the treatment of humans, however, more and more frequently recombinantly prepared aprotinin is being used.
In tissue sealants, aprotinin is used in an amount of from 20 to 3000 kallikrein inactivator units (KIU)/ml tissue adhesive as a rule, its optimum concentration depending on the fibrinolytic activity of the respective tissue. However, it has been shown that mainly in tissues with high fibrinolytic activity, the fibrinolysis-inhibitory action of aprotinin can be controlled to a very limited extent only, despite the use of high aprotinin concentrations, and thus undesired, early lytic processes may occur.